Redundancy in the World of MAP Kinases: All for One

Abstract

The protein kinases ERK1 and ERK2 are the effector components of the prototypical ERK1/2 mitogen-activated protein (MAP) kinase pathway. This signaling pathway regulates cell proliferation, differentiation and survival, and is essential for embryonic development and cellular homeostasis. ERK1 and ERK2 homologs share similar biochemical properties but whether they exert specific physiological functions or act redundantly has been a matter of controversy. However, recent studies now provide compelling evidence in support of functionally redundant roles of ERK1 and ERK2 in embryonic development and physiology. In this review, we present a critical assessment of the evidence for the functional specificity or redundancy of MAP kinase isoforms. We focus on the ERK1/ERK2 pathway but also discuss the case of JNK and p38 isoforms.

Keywords: ERK1/2; JNK; MAP kinases; functional redundancy; mouse genetics; p38; signal transduction.

Figure 1

Functional redundancy within the MAP kinase family: a model to reconcile biochemical and genetic evidence. The expression levels of MAP kinase isoforms are shown on the top and the resulting activation levels are illustrated graphically as global MAP kinase activity. A threshold of activity is required for normal biological output. MAP kinase isoforms are activated by upstream MAP kinase kinases indiscriminately and the resulting global MAP kinase activity depends on the level of expression of the individual isoforms. (A) In normal physiological conditions, both MAP kinase isoforms are activated with the predominantly expressed kinase contributing to most activity. (B) Reduced MAP kinase expression results in decreased global MAP kinase activity but the activity remains above threshold resulting in normal phenotypic outcome as exemplified by compound heterozygotes (ERK1/2, JNK1/2, or p38α/β). (C) Further reduction of MAP kinase expression (by depletion of the predominant kinase isoform) lowers global MAP kinase kinase activity below the threshold and results in developmental defects (ERK2 or p38α) or deficient cell proliferation (ERK2, JNK1). (D) Overexpression of the less predominant kinase restores global MAP kinase activity above threshold and rescues the phenotypes associated with the loss of the predominant kinase (transgenic ERK1). Note that in this model, the maximum level of MAP kinase activity is dictated by upstream activators such that the same global activity is observed under normal or MAP kinase overexpression conditions.